Project Summary/Abstract We request funds to purchase a Carl Zeiss Lightsheet Z.1 microscope. The Lightsheet Z.1 will be the first shared resource lightsheet microscope at Vanderbilt and will be integrated into the Vanderbilt Cell Imaging Shared Resource (CISR). The Lightsheet Z.1 is crucial to support the ongoing NIH-funded research of 5 Major User and 4 Minor User groups representing multiple departments within Vanderbilt University and Vanderbilt University Medical Center. These investigators have essential needs for advanced imaging of neural development, embryonic development, pancreas formation, diabetes, addiction, digestive diseases, stem cells, brain cancer, and more. We expect that numerous other NIH-funded projects will be well supported by this instrument, particularly those that require live sample and large organ/tissue imaging. We chose the Lightsheet Z.1 as the optimal instrument based on three main goals: 1) to improve the capabilities for high resolution/large field of view imaging for large tissue/organ/embryo samples, 2) to increase acquisition speed for large Z-stack/tiled imaging and live imaging, and 3) to reduce phototoxicity and photodamage to samples, including live samples, compared to traditional confocal and epifluorescent techniques. The requested instrument is configured based on the needs of the Major and Minor Users with significant consideration given to optical performance and the variety of objective lenses, live imaging capabilities, high-speed image acquisition with a dual-camera, dual-illumination system, and processing capabilities for big data and 3D/4D data sets. The specifications are fundamental to the successful implementation of the advanced imaging described in the Major and Minor User projects. The instrument will be located in Light Hall (Room 742) and maintained by the Cell Imaging Shared Resource (CISR). This room is the main CISR microscopy facility, maintained exclusively by the CISR, for the benefit of all Vanderbilt investigators. This space is secure and easily accessible to all Major/Minor users. The expertise and institutional support for this instrument are exceptional. The CISR has a 21-year history of assisting over 275 investigator labs with cutting-edge imaging expertise and cooperative research support. Dr. Matthew Tyska, Scientific Director of the CISR, and Dr. Jenny Schafer, Managing Director of the CISR, along with several experienced CISR microscopists will provide guidance, assistance, and management of the Lightsheet Z.1 microscope. To support this resource, Vanderbilt University has committed $130,000 to promote the long-term operation of the instrument.